Various approaches to the production of reversibly gelling solutions have been developed over the years. Principal efforts have been devoted to the development of gelatinous drug delivery systems for topical and subcutaneous applications and, more recently, for the administration of ophthalmic drugs to the eye. In general, sustained release drug delivery systems incorporate pharmaceutical agents in solid or semi-solid vehicles which are applied to or implanted under the skin of a patient by medical personnel. Additionally, unlike conventional drug delivery systems, ocular drug delivery systems also must address the additional problem of drug loss through the lacrimal drainage system as well as the needs of patient comfort and ease of administration.
Early approaches to the solution of the problems associated with ocular drug delivery systems utilized semi-solid ointments or gels applied directly to the conjunctive or cul-de-sac of the eye to retain the pharmaceutical agents contained therein on the ocular surface against such physiological factors as tear turnover, tear drainage, blinking, and other mechanical losses. For example, U.S. Pat. Nos. 3,944,427 and 3,700,451 disclose gelatinous drug delivery compositions containing agar, xanthine gum, and carob gum in liquid mediums in order to enhance their residence time upon the skin or mucosas and the resultant bioavailability of the medicinal products contained therein. Similarly, European Patent Application No. 0 300 888 A1, filed Jul. 18, 1988, recently disclosed the use of rhamsan gum to thicken ophthalmic compositions for droppable and topical application.
Though effective at increasing drug retention times, lack of patient acceptability remains as a significant drawback to the use of such known viscous drug delivery compositions in the eye. Many patients experience difficulty in applying the appropriate amount of such compounds to the eye and resist the unpleasant side effects of eyelid crusting and vision blurring. As a result, these compounds may only be suitable for use in the evening or during non-active hours.
A known alternative approach to these problems was the use of a formulation which is liquid at room temperature but which forms a semisolid solid when warmed to body temperature. Such a thermally triggered system is disclosed in U.S. Pat. No. 4,474,751, where an aqueous drug delivery system that forms a semi-solid "gel" at body temperature is formed from proprietary polymers known as "Tetronic.RTM." polyols. Generally speaking, these compositions are formed from approximately 10% to 50% of the specific polymers in an aqueous base. By adjusting the pH of these drug delivery systems through the addition of buffering agents, the gelling transition temperature can be raised to physiological temperatures on the order of 35.degree. C.
Similar drug delivery systems which can be injected subcutaneously or intramuscularly are disclosed in U.S. Pat. No. 4,474,752. These compounds also contain from 10% to 50% by weight Tetronic.RTM. polymers and gel at temperatures from about 30.degree. to 100.degree. C.
A thermal setting gel drug delivery system is also described in U.S. Pat. No. 4,188,373, utilizing "Pluronic.RTM. polyols" as the thermally gelling polymer. Adjusting the concentration of the polymer gives the desired "sol-gel" transition temperature. However, producing a compound which sets at physiologically useful temperature ranges limits the available viscosity of the gelled product.
Alternatively, it has been proposed to utilize formulations which gel in response to changes in pH as drug delivery vehicles. By carefully controlling the pH of such mixtures, a solution which forms a gel upon mixing with aqueous tear fluid could theoretically be produced. However, it is believed that the relatively high buffering capacity of such pH responsive compositions can lead to slow gelling, irritation and discomfort in patient eyes.
Though successful at achieving increased drug retention times, the relatively high polymer concentrations required by such formulations undesirably increase both the buffering capacity and the amount of thermal energy necessary to induce gelation of the compounds which may lead to irritation and discomfort when used in the eye. What is more, the high polymer concentrations also contribute to unacceptably high product costs and generally slow the gelling process as well, leading to migration of the compounds from the site of application or injection.
Accordingly, it is a principal object of the present invention to provide a reversibly gelling polymer solution having significantly lower polymer concentrations than has previously been attainable by the prior art in order to reduce both the buffering and thermal capacities of the solution to ensure its rapid and complete transition from liquid to gel upon application to a physiological system such as an oral dosage, the surface of the eye, or an injectable drug depot.
It is a further object of the present invention to provide a reversibly gelling solution which can be utilized as a drug delivery vehicle or wetting solution that can easily be administered by a patient in the form of a freely flowing liquid or drops which gel immediately following administration with minimal side effects, thereby providing ready patient control of drug dosage and improved patient acceptability.
It is a further object of the present invention to provide an oral dosage, drop-instillable, injectable or other depot form drug delivery vehicle which will prolong drug contact time for improved bioavailability and for sustained drug release.